Clinical Cancer Research Bridging the Lab and the Clinic in Cancer Medicine Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Clinical Cancer Research Vol. 10, 1871-1874, March 2004
© 2004 American Association for Cancer Research

Clinical Trials

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Monika E. Hegi1,4, Annie-Claire Diserens1, Sophie Godard1, Pierre-Yves Dietrich7, Luca Regli2, Sandrine Ostermann5, Philippe Otten8, Guy Van Melle6, Nicolas de Tribolet2,3 and Roger Stupp5

1 Laboratory of Tumor Biology and Genetics of the Neurosurgery Departments of the University Hospitals, 2 Lausanne and 3 Geneva; 4 National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges; 5 Multidisciplinary Oncology Center, 6 Institute of Social and Preventive Medicine, University Hospital, Lausanne; 7 Department of Oncology, University Hospital, Geneva; and 8 Division of Neurosurgery, University Hospital, Fribourg, Switzerland

ABSTRACT

Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy.

Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR.

Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression).

Conclusions: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.




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Copyright © 2004 by the American Association for Cancer Research.